Barbieri Thesis - BioMedical Materials program (BMM)

Chapter 1 – Introduction
regeneration and cancer proliferation. Paracrine signalling occurs when cells of
different types secrete the ligands, which diffuse towards the nearby target cells and
bind to their receptors. This mechanism is common, for instance, during connective
tissue repair, where macrophages secrete cytokines pushing fibroblasts to proliferate
and synthesize new matrix. Sometimes, e.g. during inflammation reactions, endocrine
organs produce biomolecules that, via the blood and lymph streams, reach and affect
distant target cells. In natural tissues, the cellular fate is driven by a number of
proteins, i.e. the growth factors, which promote various cellular phenomena
controlling the health of tissues (Table 2). Further to biochemical instruction, it has
been reported that physical stimuli from the surrounding micro–environment can
influence cellular behavior as well. For instance, in addition to its role as a molecule
transporter, the interstitial fluid flow in tissues mechanically acts on fibroblast and
smooth muscle cells promoting their motility [97] and it has been suggested inducing
fibroblasts to proliferate and differentiate into contractile myofibroblast in vitro. [98]
Interestingly, fluids can also induce osteocytes to secrete molecules that later trigger
bone remodeling (see the key concept box 2). From here, a possible role of the flow
of fluids in inducing muscular tissue regeneration is seen. In vitro studies have shown
that the stiffness of polymeric substrates can instruct cultured marrow–derived
mesenchymal stem cells to differentiate into either a neuronal, myoblastic or
osteoblastic lineage. [99–104] As the body tissues vary in their structure (e.g. brain tissue
offers softer structure than bone), it is plausible that the stiffness of the interstitial
matrix may control in vivo the fate of stem cells. Other instructive signals that cells
can perceive might be the forces caused by the cellular binding to the interstitial
matrix through different molecules (e.g. fibronectin and vitronectin), [105] or the
topography of the tissue (e.g. orientation of the fibers in interstitial matrix may induce
stem cells to differentiate into cells having certain polarity, such as myoblasts). [105–107]
1.7. When the body fails – aiding tissue regeneration and repair
Largely injured tissue environments may lose their instructing properties and, without
adequate or sufficient stimuli, stem cells may not be able to regenerate or repair the
tissue. This may happen, for example, in myocardial tissue after infarction [84] or in
bone defects where large quantities of tissue are missing (i.e. critical sized bone
defects). [85, 86] In such situations there is need of external intervention to support the
cellular activity with stem cells or gene therapies, by grafting with healthy harvested
tissues and organs (i.e. auto– and allografts) or biomaterials.
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